Although significant advances have been made in recent years in the development of treatments for cancer, many of the resulting treatments are still based on administration of toxic compounds with consequential side-effects. As an alternative form of therapy, attempts have been made to enhance the patient's own immune response against tumours with varying degrees of success. It is not really understood how tumour cells escape recognition by the host immune system and/or inhibit an immune response. For example, it has been known for several years that a variety of immune cell-types infiltrate solid tumours in large numbers yet fail to mount an effective immunological response to the tumour. Indeed, it is possible to isolate tumour infiltrating lymphocytes which contain T cells with T cell receptors specific for tumour antigens in vitro which fail to be activated by tumour tissue in vivo. Thus there is need in the art for therapeutic methods that are capable of overcoming this immunosuppressive effect exerted by tumour cell in vivo.
Ligands that bind to cell surface receptors of the Notch family have recently been shown to be expressed on the surface of cells of the immune system, such as antigen presenting cells (APCs) and T-lymphocytes and a role for these molecules in such cells has been demonstrated in the regulation of tolerance induction (WO-A-98/20142).
It has recently been shown that it is possible to generate a class of regulatory T cells which are able to transmit antigen-specific tolerance to other T cells, a process termed infectious tolerance (WO-A-98/20142). The functional activity of these cells can be mimicked by over-expression of a Notch ligand protein on their cell surfaces. In particular, regulatory T cells can be generated by over-expression of a member of the Delta or Serrate family of Notch ligand proteins. Delta or Serrate expressing T cells specific to one antigenic epitope are also able to transfer tolerance to T cells recognising other epitopes on the same or related antigens, a phenomenon termed “epitope spreading”.